Randomized intermittent or continuous panitumumab plus FOLFIRI (FOLFIRI/PANI) for first-line treatment of patients (pts) with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC): The IMPROVE study.
Authors: Antonio Avallone, Francesco Giuliani, Guglielmo Nasti, Vincenzo Montesarchio, Giuseppe Santabarbara, Silvana Leo, Alfonso De Stefano, Gerardo Rosati, Ivan Lolli, Emiliano Tamburini, Alfredo Colombo, Daniele Santini, Lucrezia Silvestro, Gaetano Facchini, Francesco Mannavola, Antonio Febbraro, Giancarlo Troncone, Alberto F. Sobrero, Diana Giannarelli, Alfredo Budillon
Journal: Journal of Clinical Oncology (2022)

3503 Background: Continuous anti-EGFR-based FOLFIRI is a first-line standard of care in pts with RAS/BRAF wt mCRC. The emergence of resistance and treatment-related toxicity limit the efficacy of continuous treatment. Thus, an intermittent strategy could reduce both toxicity and resistance. Methods: This is a prospective, randomized, non-comparative, open-label, multicenter phase II study. Unresectable, previously untreated RAS/BRAF wt mCRC pts, were randomized to a control arm (A) receiving FOLFIRI/PANI continuously until progression or to the experimental arm (B), receiving 8 cycles of the same regimen followed by a treatment free interval. This lasted untill progressive disease, when another treatment period of up to 8 cycles was restarted. This intermittent strategy was continued until progression occurred on treatment. Tumor assessment was always done every 8 weeks in both arms. Pts were stratified for center, ECOG PS (0-1 vs 2), previous adjuvant therapy (yes or no), sidedness (right vs left) and metastatic sites (1 vs ≥ 2). The primary endpoint was the progression-free survival on treatment (PFSOT) at 1 year. Assuming p1=43% PFSOT at 1 year, corresponding to an expected median PFSOT time ≥ 10 months in the experimental arm, and a 5% drop-out rate, a sample size of 68 pts in each arm granted the study a power of 80%, with a type I error of 10% (binomial test) for rejecting the null hypothesis, p0=30%, corresponding to a median PFSOT time of ≤ 7 months. Secondary endpoints were safety, quality of life, OS and response rate (ORR); ctDNA samples were also collected. No formal comparison between the two arms was planned. Results: From May 2018 to June 2021, 137 pts were randomized (69 arm A/68 arm B). Main pts’ characteristics were (arm A/B): males 59/61%; median age 62/66yrs; PS 0 84/72%; right colon 17/15%; previous adjuvant therapy 22/29%; single metastatic site 33/26%. At a median follow-up of 18 months (IQR: 10-26), median PFS OT was 12.6 months (95% CI: 9.0-16.1) in arm A and 17.6 months (95% CI: 7.5-27.8) in arm B with a 1 year PFSOT rate of 51.7% and 61.3%, respectively. ORR (arm A/B) was 64/56%. Median number of FOLFIRI/PANI cycles administered per patient were (arm A/B) 13/12. Main grade 3-4 toxicities were (arm A/B): skin 27/13%, neutropenia 23/22%; diarrhea 13/15%. Conclusions: The primary endpoint of the study was met with the intermittent FOLFIRI-PANI strategy producing a long PFS with a reduced skin toxicity. These data deserve further investigations in a phase III trial. Clinical trial information: NCT04425239.